A new, hypervirulent clinical variant of Klebsiella pneumoniae (hvKP) has emerged over the last decade. Initial reports were from the Pacific Rim, but more recently hvKP has been described in the United States, Canada, Europe, Israel, Australia, South Africa and elsewhere. At first, infection due to hvKP was characterized and distinguished from traditional infections due to classical K. pneumoniae (cKP) by: 1) presenting as community-acquired hepatic abscess, 2) affecting patients lacking a history of hepatobiliary disease, and 3) a propensity for causing metastatic spread to distant sites in 11-80% of cases (e.g. eyes, central nervous system (CNS), & others). More recently, hvKP has also been described to cause a variety of serious extrahepatic abscesses/infections as well. hvKP is associated with a significant mortality rate, ranging from 3-32% depending on the study. Survivors with metastatic spread often suffer catastrophic morbidity such as loss of vision and neurologic sequelae. From a clinical perspective, hvKP possesses novel features for an enteric Gram-negative bacillus (GNB). Metastatic spread is common for certain Gram-positive pathogens such as Staph and Strep, but is uncommon enteric GNB (e.g. E. coli and cKP). The basis for this change is poorly understood. One of the goals of this proposal is to fill that knowledge gap by identifying novel or unrecognized pathogenic traits of hvKP that contribute to its hypervirulence. Compounding an already challenging clinical situation is the recent propensity of K. pneumoniae to become multi-dug resistant (MDR), including the acquisition of extended-spectrum beta-lactamases and carbapenemases. Some cases of infection due to hvKP caused by MDR-strains have already been described and as expected, outcome is worse with inappropriate treatment. As a result, management of infections due to hvKP will become extremely increasing challenging and morbidity and mortality rates will increase. The confluence of hypervirulence and MDR in hvKP has the potential to create a post-antibiotic scenario; similar to what was feared with methicillin resistant Staphylococcus aureus (MRSA) but was never realized. Therefore, enhancing our understanding of this highly virulent pathogen is critical. A novel and efficient approach is used to identify both new or unrecognized virulence factors that are specific for hvKP and are essential for extraintestinal growth/survival in vitro and in vivo. Subsequently these virulence factors will undergo initial characterization. These data will be important and unique, and will lay the foundation for understanding the biology of this new and frightening clinical variant.